1. Field of the Invention
This invention relates to a series of novel oxazole derivatives which are useful as inhibitors of ADP-induced aggregation of human blood platelets in platelet-rich-plasma.
2. Description of the Art
Platelet aggregation is considered part of a complex physiological mechanism for formation of a thrombus in the vascular system. Thromboembolic phenomena, i.e., the formation of thrombi, are involved in hemostasis and a number of diseased states in mammals including thrombophlebitis, phlebothrombosis, cerebral thrombosis, coronary thrombosis and retinal vessel thrombosis. An increase in propensity for platelet aggregation, sometimes referred to as platelet adhesiveness, is observed following parturition, surgical operations such as coronary artery bypass surgery, organ transplant, angioplasty, prosthetic heart valve implants to name a few; and in ischemic heart disease, atherosclerosis, multiple sclerosis, intracranial tumors, thromboembolism, and hyperlipemia (A. Poplawski, et al, J. Atherosclerosis Research, 8:721 (1968)).
Octimibate (i) is a broad spectrum inhibitor of platelet aggregation; IC.sub.50 =1 .mu.g/ml (human PRP vs ADP). (a. U.S. Pat. No. 4,460,598 b. Lautenschlager, et al., Drugs of the Future, 11, 26 (1986)). ##STR3##
EPO 0434034, to Meanwell, et al., discloses (ii), which is an orally active broad spectrum inhibitor of platelet aggregation. ##STR4##
Lautenschlager, et al., U.S. Pat. No. 4,460,598 issued Jul. 17, 1984 describe a series of triphenylimidazol-2-yloxyalkanoic acids having the formula (iii) ##STR5## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each are H, halogen alkyl, alkoxy and trifluoromethyl; n is an integer of 1 to 10 and R.sup.7 is H, alkali metal ions, alkyl or benzyl group. The compounds of U.S. Pat. No. 4,460,598 are reportedly useful in the treatment of thromboembolic, inflammatory and/or atherosclerotic disease in man. A particularly preferred member of the series wherein R.sup.1 to R.sup.6 is hydrogen, n is 7 and R.sup.7 is sodium (identified in the art as octimibate sodium) has been described as possessing anti-aggregatory activity.
Meanwhile, N. A., European Patent Application 0434034 further describes oxazole derivatives having formula (iv) or (v) ##STR6## wherein n is 7-9 and R is hydrogen or lower alkyl ##STR7## wherein R.sup.1 and R.sup.2 are each phenyl or thienyl; R.sup.3 is hydrogen, lower alkyl or together with CO.sub.2 is tetrazol-1-yl; X is a divalent connecting group; and Y is a divalent connecting group attached to the 3-or 4-phenyl position. Compounds of formulas (iv) and (v) are useful as inhibitors of mammalian blood platelet aggregation.
Among the compounds disclosed in the compounds of formula (vi) identified as ##STR8##
D. L. Aldous, et al., J. Org. Chem., 1151 (1960) describe the chemistry of styryloxazoles of the formula (vii) ##STR9## wherein R is hydrogen, p-methoxy, o-hydroxy and 3,4-methylendioxy.
Brown, U.S. Pat. No. 3,578,671 describes a class of oxazole-2-polycarbon aliphatic monocarboxylic acids arylated at the 4- and/or 5-position in the oxazole ring of the formula (viii) ##STR10## in which each of the substituents R.sup.2 and R.sup.3 is a member of the group consisting of unsubstituted phenyl, naphthyl, thienyl and furyl radicals and phenyl radicals substituted by substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro and trifluoromethyl radicals; and wherein R.sup.1 is selected from the group consisting of carboxyalklyl- and carboxylalkenyl radicals each containing from 2 to 5 carbon atoms and the amides, hydroxamic acid derivatives, lower alkyl esters and lower alkanoyloxy-lower-alkyl esters thereof. The compounds of U.S. Pat. No. 3,578,671 include the clinically effective anti-inflammatory agent known generically as oxaprozin (R.sup.2 =R.sup.3 =phenyl, R.sup.1 =(CH.sub.2).sub.2 CO.sub.2 H).
Meanwell, U.S. Pat. No. 5,187,188 describes compounds of the structure (ix) ##STR11## wherein Y and Z are independently hydrogen or together form a bond; X is CN, CO.sub.2 R.sup.1 or CO.NR.sup.2 R.sup.3 ; R and R.sup.1 are independently or together H, Na, or C.sub.1 -C.sub.5 lower alkyl; R.sup.2 and R.sup.3 are independently or together H, or C.sub.1 -C.sub.5 lower alkyl.